Phosphoinositide 3-kinases (PI3Ks) are ubiquitous lipid kinases, functioning not only as a signal transducer downstream of a receptor at a cell surface but also as a signal transducer in constituent intracellular membrane and protein trafficking pathways (Vanhaesebroeck, B. et al., Nature Rev. Mol. Cell Biol., 2010, 11, 329-341). The PI3K family of lipid kinases can be divided, based on their physiological substrate specificity, into three classes: Class I, Class II, and Class III. Among these three classes, Class I has been widely studied. Class I PI3Ks are heterodimers composed of a p110 catalytic subunit and a regulatory subunit. Class I PI3Ks are further divided into Class Ia kinases and Class Ib kinases. Class Ia kinases are composed of three different catalytic subunits (p110α, p110β and p110δ), which dimerize with five different regulatory subunits (p85α, p55α, p50α, p85β, and p55γ), wherein all the catalytic subunits can interact with all the regulatory subunits to form various heterodimers, which are called PI3Kα, PI3Kβ, and PI3Kδ. p110α and p110β are expressed essentially in all cell types, while p110δ is expressed primarily in leukocytes. The single-type Class Ib kinases are composed of p110γ catalytic subunits interacting with p101 regulatory subunits, and are called PI3Kγ. Like p110δ, Class Ib kinases are expressed primarily in leukocytes.
PI3Ks play a role in tumorigenesis in many kinds of cancers, due to the dysregulation or overactivation of PI3K/AKT pathway (Vivanco and Sawyers, Nature Rev. Cancer, 2002, 2, 489-501). Among the four isoforms, PI3Kδ plays a role in controlling the survival of B-cells in certain B-cell cancers. For example, PI3Kδ is important to the survival of non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL). It has been clinically proven that PI3Kδ inhibitor, idelalisib, is capable of treating CLL (Furman, R. R., et al., The New Englang Journal of Medicine, 2014, 370, 997-1007; O'Brien, S., et al., Blood, 2015, 126, 2686-2694), and thus it has been approved by the US FDA for treatment of these diseases. This adequately shows that B-cell lymphoma and leukemia including NHL and CLL can be treated by inhibiting the activity of PI3Kδ.
In addition, inhibition of PI3Kδ can break regulatory T-cell-mediated immune tolerance to tumors, and increase immune responses, thus leading to regression of a tumor in an animal model (Ali, K. et al., Nature, 2014, 510, 407-411). These findings show that inhibition of PI3Kδ is valuable to the treatment of tumors, especially those with insufficient immune response, such as, breast cancers, lung cancers (including small cell lung cancer, non-small cell lung cancer, and bronchioloalveolar carcinoma), prostate cancers, cholangiocarcinoma, bone cancers, bladder cancers, head and neck cancers, renal cancers, liver cancers, gastrointestinal tissue cancers, esophageal cancers, ovarian cancers, pancreatic cancers, skin cancers, testicular cancers, thyroid cancers, uterine cancer, cervical cancers, vaginal cancers, leukemia, multiple myeloma, lymphoma, etc.
In addition to tumors, evidence also show that PI3Kδ also plays an important role in inflammations and autoimmune diseases (Puri, K. D. et al., J. Immunol., 2009, 182 (Suppl. 50), 14; Maxwell, M. J. et al., J. Autoimmunity, 2012, 38, 381-391; Suarez-Fueyo, A. et al., J. Immunol., 2011, 187, 2376-2385). Thus, inhibition of PI3Kδ can be used for treatment of inflammatory diseases and autoimmune diseases, including but not limited to, dermatitis, rheumatoid arthritis, allergic rhinitis, asthma, Crohn's disease, chronic obstructive pulmonary disease (COPD), systemic lupus erythematosus, psoriasis, multiple sclerosis, activated PI3Kδ syndrome, Sjogren syndrome, etc.
The present application relates to a new generation of PI3K inhibitor which can be used in treatment of cancers, inflammatory diseases, and autoimmune diseases.